Atomoxetine is the (R)-(−)-enantiomer of Tomoxetine, is an 3-aryloxy-3-phenyl propylamine structurally represented by the compound of Formula-I, a selective norepinephrine reuptake inhibitor, marketed as hydrochloride salt under the name of STRATTERA® used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). It is about 2 times effective than racemic mixture, about 9 times effective than (+)-enantiomer and exhibits less anticholinergic side effects as disclosed in U.S. Pat. No. 4,018,895, EP 0 052 492 and EP 0 721 777.
U.S. Pat. No. 4,314,081 discloses a process for preparation of N-methyl-3-(o-tolyloxy)-3-phenylpropylamine hydrochloride along with other compounds. One of the disclosed process for preparation of N-methyl 3-(o-tolyloxy)-3-phenylpropylamine involves the reaction of N,N-dimethyl-3-phenyl-3-chloro propyl amine hydrochloride with sodium salt of the corresponding phenol in methanol followed by demethylation using cyanogen bromide in benzene. The demethylated compound resolved by unspecified procedure and subsequently converted to hydrochloride salt by using gaseous hydrogen chloride.
The reaction of N,N-dimethyl-3-phenyl-3-halopropyl amine hydrochloride with sodium salt of the corresponding phenol in methanol is a time consuming process, requires about five days for completion of reaction. The whole process involves several unit operations. Further involves use of commercial grade o-cresol at plant level which contains phenol, p-cresol and 2,6-xylenol as impurities. These impurities can be carried forward to the final stage; hence exhaustive purification is required to remove the impurities. Use of benzene, thionyl chloride, cyanogen bromide and dry HCl gas are also major drawbacks of the process and makes it unattractive from the safety point of view, environmentally, economically and industrially. Moreover, the patent is silent about purity and yield of the atomoxetine or salts thereof.

The alternate process disclosed in same U.S. Pat. No. 4,314,081 involves the bromination of 3-phenylchloropropyl amine with N-Bromosuccinimide (NBS) in presence of benzoyl peroxide in carbon tetrachloride. The bromination reaction is exothermic reaction. The brominated compound is condensed with dry sodium salt of o-cresol followed by amination with methyl amine at temperature as high as 140° C. for 12 hours. The aminated compound is resolved by unspecified procedure to give atomoxetine.

The main disadvantages of the process are use of reagents like N-bromosuccinimide which is a corrosive chemical, unfavorable condition like high vacuum (0.03 torr) distillation of condensed chloro compound at temperature 135-145° C. The process is tedious and time consuming as amination is conducted at 140° C. at pressure of 10 kg/cm2 for 12 hours in autoclave. Further, the patent is silent about purity and yield of the atomoxetine or salts.
EP 0 052 492 discloses (−)-enantiomer of tomoxetine i.e. atomoxetine and process for the preparation thereof, wherein tomoxetine is prepared by demethylating N,N-dimethyl 3-(o-tolyloxy)-3-phenylpropylamine by reaction with phenyl chloroformate in toluene to form carbamate intermediate and hydrolyzing the same with sodium hydroxide in the presence of propylene glycol to form tomoxetine. Tomoxetine is then treated with (S)-(+)-mandelic acid followed by basification and extraction in diethyl ether. The resulting atomoxetine is treated with hydrogen chloride gas to afford atomoxetine hydrochloride. Atomoxetine hydrochloride is then recrystallized from ethyl acetate, dichloromethane and diethyl ether. The patent describes the use of propylene glycol which is a costly reagent, hence not recommended on industrial scale. Further the demethylation reaction involves very long and tedious procedure for reaction as well as workup, and then demethylated compound is crystallized by triturating with hexane and recrystallized by diethyl ether and methylene chloride.
U.S. Pat. No. 6,541,668 discloses a process for the preparation of atomoxetine hydrochloride involves reacting an alkoxide of N-methyl-3-phenyl-3-hydroxy propyl amine or an N-protected derivative thereof, with 2-fluorotoluene at temperature 110° C. for 20 hours in 1,3-dimethyl-2-imidazolidinone (DMI) or N-methyl-3-pyrolidinone (NMP) as solvents. Further the process persists to form (S)-(+)-mandelate salt with the help of seeding (R)-tomoxetine (S)-(+)-mandelic acid salt. Then (R)-tomoxetine (S)-(+)-mandelate salt is basified and extracted with methyl t-butyl ether. Water is removed by azeotropic distillation and hydrogen chloride is added to give atomoxetine hydrochloride.

The main disadvantages of the above process is to use the solvent like DMI is well known for its toxic effect in contact with skin and NMP has been identified as a reproductive toxicant, first by California office of environmental health hazard assessment (OEHHA) in 2001. This process involves disadvantages as long reaction time, tedious and more number of operations and large solvent volumes those are incompatible with large-scale industrial synthesis. Moreover, the patent does not disclose product yield and purity as well.
U.S. Pat. No. 7,507,861 discloses a process for the preparation of atomoxetine hydrochloride as described below: N-methyl-3-hydroxy-3-phenylpropylamine is taken in dimethyl sulphoxide and potassium hydroxide and heated to 110° C. Then the mixture is vacuum distilled to remove 130 gm solvent from 1100 gm. After this procedure 2-fluorotoluene is added to the reaction mass and heated as high as 145-147° C. Then water and toluene is added. After separation of organic phase the reaction proceed to prepare (R)-(−)-tomoxetine (S)-(+)-mandelate. The reaction involves (R)-(−)-tomoxetine (S)-(+)-mandelate in toluene and water (1:1) treating with 30% sodium hydroxide solution to convert (R)-(−)-tomoxetine (S)-(+)-mandelate into (R)-(−)-tomoxetine free base. The phase are separated and concentrated the organic layer to give (R)-(−)-tomoxetine free base oil. The obtained free base oil is dissolved into 9 volumes of ethyl acetate at low temperature about 12° C. followed by addition of gaseous hydrogen chloride to give atomoxetine hydrochloride.

The main disadvantage of the process is distillation in first stage makes the process unattractive from the operation point of view. Use of gaseous hydrogen chloride is very much critical to handle at the plant level. Moreover, gaseous hydrogen chloride generates white fumes upon contacting with humidity which can be hazardous to the health when inhaled. As per the observation of scientist of the present invention that in the first stage of condensation, the continuous removal of water is necessary to complete the reaction otherwise reaction will remain incomplete and needed more efforts to remove impurities from the incomplete reaction.
WO 2006/037055 A1 discloses the (±)-atomoxetine oxalate having crystalline form II. As disclosed in the below scheme, the process for preparing oxalate salt of tomoxetine is very lengthy, cumbersome and several operations make the process industrially uneconomical as well as unviable. Moreover that the yield obtained is 55% after very lengthy process, which is not satisfactory from the industrial point of view. Again preparation of (S)-(+)-mandelate salt from the oxalate salt is also not attractive due the use of various solvents including petroleum ether. Use of autoclave and treatment of the material with two different alkalis is not understandable or unjustifiable from the chemistry point of view. Three time distillation at the condensation stage make the process very lengthy, cumbersome and unattractive from the plant point of view. Purification at condensation stage with acetone and petroleum ether leads the process to loss of yield. Further the conversion to atomoxetine hydrochloride gives around 73% yield. The process is depicted in below scheme.

WO 2008/062473 A1 discloses the process for the preparation of atomoxetine hydrochloride starting from the condensation of o-cresol and N,N-dimethyl-3-chloro-3-phenyl-propylamine to form N,N-dimethyl-3-(o-methylphenoxy)-3-phenyl-propylamine followed by demethylation by treating with phenyl chloroformate in the presence of triethylamine and subsequently reacted with oxalic acid to isolate oxalic acid salt of tomoxetine having crystalline form I converted to (±)-atomoxetine free base which is then reacted with (S)-(+)-mandelic acid to form (S)-(+)-mandelic acid salt of (R)-tomoxetine. The obtained salt is treated with alkali and converted to atomoxetine hydrochloride by treatment with IPA-HCl. The yield is as low as about 71%. The disclosed process is operationally very lengthy and tedious as depicted in the below process scheme. In condensation stage lots of operations are involved which make it very cumbersome. The process involves additional operation like demethylation which leads to loss of yield. Moreover this, use of industrial o-cresol at large scale is not a good option as commercial o-cresol contains contamination of p-cresol, phenol, 2,6-xylenol which can be carried forward up to the last stage of API; hence exhaustive purification is required to remove the impurities.

WO 2006/020348 discloses the crystalline polymorphic forms, Form A, Form B and Form C of Atomoxetine hydrochloride. WO 2006/020348 further discloses that the repetition of the processes disclosed in EP 052,492 and U.S. Pat. No. 6,541,668 yielded a crystalline form of Atomoxetine hydrochloride denominated as Form A.
Thus, present invention fulfills the need of the art and provides an improved and industrially applicable process for preparation of atomoxetine hydrochloride, which provides atomoxetine hydrochloride in high purity and good yield.